Because of their large size compared to small molecules, and their multi-functionality, nanoparticles hold promise as biomedical imaging, diagnostic, therapeutic, and theragnostic agents. However, the key to their success hinges on a detailed understanding of their behavior after administration into the body. The biodistribution, target binding, and clearance of nanoparticles are a complex function of their physicochemical properties in serum, which include hydrodynamic diameter, solubility, stability, shape and flexibility, surface charge, composition, and formulation. Moreover, many materials used to construct nanoparticles have real or potential toxicity, or may interfere with other medical tests. In this talk, the design parameters that mediate nanoparticle behavior in the body and the fundamental principles that govern clinical translation will be discussed. By analyzing those nanomaterials that have already received regulatory approval, we attempt to predict which types of nanoparticles hold potential for clinical translation. Finally, using quantum dots as an example, we provide a framework for deciding whether a nanoparticle-based agent is the best choice for a particular clinical application.